The broad, long-term objective of the proposed research is the development of chelating agents which are effective in the treatment of both acute and chronic cadmium intoxication. Cadmium intoxication is presently a condition for which there is no accepted clinical treatment. The specific aims are (1) To continue the synthesis and testing of new chelating agents of low toxicity which are capable of acting as antagonists for acute as well as chronic cadmium intoxication. These will be primarily dithiocarbamates and vicinal dithiols and they will be evaluated in rodent models under conditions of both chronic and acute exposure. They will be examined especially for their ability to reduce total cadmium body levels in rodents with aged cadmium deposits. (2) To examine several of the histopathological aspects of cadmium mobilization and to determine if the chelate induced excretion of cadmium from animals with chronic cadmium intoxication can be related to renal cadmium burdens. The main goal of the histopathological studies will be to determine the conditions under which cadmium can be mobilized from the kidney and the liver without causing any deterioration in renal function. The development of a simple model which relates chelate induced cadmium excretion in the urine to renal cadmium levels would be extremely useful in screening individuals with chronic cadmium intoxication. (3) To determine which chelating agents are the most effective in the treatment of acute cadmium intoxication in mice. (4) To develop a more effective model for the chelate therapy of cadmium intoxication and its management by the use of chelating agents. Related basic chemical information on the kinetics of cadmium reactions which is needed to put such a model on a firm basis will also be collected. The chemical information needed is primarily information on the rates of reactions of species such as cadmium metallothionein with chelating agents.